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Background

Epidermolytic ichthyosis (EI), previously termed bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a clinically heterogeneous genodermatosis caused by mutations in the genes encoding the suprabasal keratins 1 and 10. Classical EI is clinically characterized by severe neonatal erythroderma, blistering and fragile skin in infancy, quickly subsiding with subsequent development of generalized scaling hyperkeratosis. We report three Dutch families with palmoplantar keratoderma and mild blistering, but without neonatal erythroderma and generalized scaling. A novel heterozygous missense mutation in the linker L12 domain of KRT1:c.1019A>G, p.Asp340Gly was found associated with this phenotype in these families.

Objectives

To investigate the effects of the novel KRT1:p.Asp340Gly and the one other previously reported KRT1:p.Asp340Val mutations on keratinocyte cytoskeleton formation and stress resistance.

Methods

Wild-type and mutant pEGFP-KRT1 fusion constructs were transfected into HaCaT cells and exposed to hypo-osmotic shock. Haplotyping and genealogical studies were performed to investigate the possibility of a common founder for p.Asp340Gly.

Results

Cells transfected with either one of the keratin 1 L12 domain mutations showed significantly increased tonofilament aggregation. The haplotype around the KRT1 gene was shared in all affected family members of two families and a common founder was traced.

Conclusions

Our study supports the pathogenicity of the keratin 1 L12 domain mutations in vitro. These mutations are associated with a milder EI phenotype with pronounced palmoplantar keratoderma, and without neonatal erythroderma and scaling. The KRT1:p.Asp340Gly mutation in the Dutch families is likely to have arisen from a common founder."xsd:string
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http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/author"Willemsen M."xsd:string
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/author"van Geel M."xsd:string
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/author"van Steensel M.A."xsd:string
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/author"Jonkman M.F."xsd:string
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/author"Bolling M.C."xsd:string
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/author"Bladergroen R.S."xsd:string
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/date"2010"xsd:gYear
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/name"Br J Dermatol"xsd:string
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/pages"875-879"xsd:string
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/title"A novel mutation in the L12 domain of keratin 1 is associated with mild epidermolytic ichthyosis."xsd:string
http://purl.uniprot.org/citations/20500210http://purl.uniprot.org/core/volume"162"xsd:string
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